Disruptions in the glutamatergic system represent an innovative target of medications development for cocaine dependence. Our preliminary investigations with ketamine, a glutamatergic modulator with potent prefrontal effects, suggest that it represents a promising Candidate. Alongside being safely administered, with no development of psychosis or ketamine misuse, we found that sub-anesthetic ketamine led to significant changes in measures of motivation to stop cocaine use, when compared to an active control (n=8). Further, ketamine had promising effects on cue-induced craving. This project aims to examine whether these promising effects extend to cocaine self- administration. We will evaluate the effect of a single sub-anesthetic dose of ketamine (0.11 mg/kg over 2 minutes, followed by 0.60 mg/kg over 50 minutes) on cocaine self- administration in 20 non-treatment seeking non-depressed cocaine-dependent individuals who complete a 9-week combined laboratory-inpatient and outpatient double- blind, cross-over, randomized, controlled study. Participants will be provided a choice session of five cocaine choices 24 hours following each active infusion. We predict that, compared to midazolam, ketamine will significantly reduce the number of cocaine choices during the choice session. Secondary aims pertain to the effect of ketamine on cocaine-related deficits that implicate prefrontal dysfunction, such as stress sensitivity, craving, impulsivity, low motivation, low self-efficacy, and low mindfulness. Thus, we aim to evaluate a highly innovative intervention in a manner that has the capacity to make important and unprecedented contributions to the field. An effect of ketamine on cocaine self-administration would suggest that brief potent glutamatergic modulation represents a possible treatment strategy for cocaine dependence that merits further investigation.